Natural killer (NK) cells are innate lymphocytes that play a pivotal role in early anti-pathogen host defense and are particularly important in mediating resistance to viral infections. Indeed, humans with selective NK cell deficiencies experience significant difficulty with herpesviruses infections. The ability of NK cells to kill abnormal cells and produce immunomodulatory cytokines and chemokines uniquely positions them to not only participate in the initial defense against intracellular pathogens but also to influence the subsequent adaptive immune response. In addition to killing infected cells and generating cytokines and chemokines, NK cells are stimulated to vigorously proliferate during viral infections. This proliferative response can be divided into three distinct phases: early nonspecific NK cell proliferation, preferential proliferation of NK cells that are able to recognize infected cells, and cessation of proliferation and contraction of the expanded NK cell population. The regulatory mechanisms involved in controlling these different phases of NK cell proliferation are poorly characterized. The long-term objective of these studies is to understand the in vivo regulation of NK cell proliferation and homeostasis during viral infections. Using murine cytomegalovirus (MCMV) infection as a model system, we propose to address several critical, unresolved issues in the in vivo regulation of NK cell proliferation and homeostasis including 1) the relative contributions of cytokines and NK cell activation receptors to viral-induced NK cell proliferation, 2) the mechanism by which NK cell activation receptor signaling augments cytokine-driven NK cell proliferation, and 3) the role of the adaptive immune system in the resolution of viral-induced NK cell proliferation. We contend that a clearer understanding of in vivo NK cell proliferation and homeostasis during viral infections will have broad translational implications and may lead to novel therapeutic interventions to modulate NK cells to either stimulate more effective responses (e.g., during intractable viral infections or solid organ malignancies) or down-regulate over-exuberant or inappropriate responses (e.g., during NK cell lymphoproliferative disorders or autoimmune diseases). Public Health Relevance: Our innate immune system provides early resistance to viral infections while the more specific adaptive immune system is being activated. The overall objective of the proposed studies is to understand the regulation of one important type of cell in our innate immune response, natural killer cells, during viral infections. A more complete understanding of natural killer cell homeostasis during viral infections may lead to new ways to modulate natural killer cell responses during viral infections or autoimmune disorders.